The present invention generally relates to therapeutic agents for the treatment of viral-induced tumors, such as warts. In one embodiment, the therapeutic agent is in the form of sandalwood oil or an isolate or isolates from the sandalwood oil described herein. Use of the oil or its components as a topical agent for the treatment of viral-induced tumors, such as human papillomavirus-induced tumors, is disclosed. The therapeutic agents in sandalwood oil were found to be xcex1- and xcex2-santalols. Use of xcex1- and xcex2-santalols in the treatment of viral-induced tumors, such as human papillomavirus-induced tumors, is disclosed.
Viruses, which induce tumors in mammals, are widespread. Indeed, there are over sixty known types of human papillomaviruses (HPV) which are DNA viruses. These viruses may induce the production of tumors. Some of these HPV""s have been associated with benign tumors, such as common warts, while others have been strongly implicated as etiologic agents in dysplasia and carcinomas in the oral and genital mucosa of the infected mammal.
Warts are a very common skin lesion in humans and are caused by various human papillomaviruses (DNA virus). Each virus is related to a specific clinical presentation of the wart. Warts are infectious and may be autoinoculated and spread to other individuals by direct contact.
Verrucae warts have a rough surface, are lumpy and typically flesh colored. Finger-like projections and sometimes dark specks are present, which are the result of thrombosed capillaries. Usually these warts are found on the face and scalp. Plantar warts are found on the planter surface of the feet and may be deep and painful. These warts occur singularly or in clusters and may be spread over a wide area. Flat warts are typically small, flat-topped, flesh colored papules that occur primarily on the face, hands and forearms. Usually the surface of the wart is smooth and they may appear in the hundreds. Genital warts are soft, flesh colored or slightly pigmented and occur in the genitalia of the mammal and may be sexually transmitted. Chronic infections that cause genital warts in women are a serious problem as intra epithelial neoplasia or squamous cell carcinoma may develop. See Oski et al., Princ. Pract. Pediatrics, 2nd ed., pp. 789-790.
There are various therapies for the treatment of warts, but none are considered truly effective as they typically fail to totally cure the lesions and do not prevent recurrence. A discussion of presently accepted therapies may be found in Stone, 1995, Cl. Infec. Diseases, Suppl. 20, pp. 991-997 and Sterling, 1995, Practioner, Jan. 239(1546), pp. 44-47. Numerous compositions are presently marketed for wart removal. One such product is Occlusal(copyright)xe2x80x94HP marketed by the GenDerm Corporation of Lincolnshire, Ill. This product is a 17% solution of salicylic acid in a polyacrylic vehicle. The Shering-Plough Company of Memphis, Tenn. produces and markets a product known as Duo Film(copyright) which is a patch containing salicylic acid. The product literature recommends that the wart be washed and dried prior to the application of a medicated patch which contains 40% salicylic acid. This patch is then covered with an additional bandage and the procedure is repeated every 48 hours until the wart is gone, which sometimes takes up to 12 weeks.
Recently, it has also been observed that individuals with depressed immune systems, such as sufferers of Acquired Immune Deficiency Syndrome (AIDS), may be prone to HPV infections which may result in tumor growth over their entire bodies, resulting in great mental and physical distress to the afflicted individual.
Current modalities for the treatment of viral-induced tumors involve the removal of the tumor by either: (1) surgical intervention (laser or operative); (2) the application of organic acids, such as glacial acetic acid and/or salicylic acid and lactic acid to xe2x80x9cburnxe2x80x9d the tumor away; (3) the injection into the tumor of an anti-tumor vaccine prepared from ground tumors; and to a lesser extent, (4) the use of a drug, such as podophyllin, interferons and fluorouracil or 5-FU; and (5) freezing.
While being useful for removing the viral-induced tumor, the current treatment modalities still suffer from one or more of the following drawbacks: (1) they may result in the destruction of healthy uninfected tissue; (2) they may result in scarring and disfigurement; (3) they may result in discomfort to the mammal being treated thereby; (4) they may result in necrosis of the tumor and the surrounding tissue may result in a secondary infection which may require treatment with an antibiotic; and (5) they do not always result in the destruction of latent viral DNA which may be maintained in surrounding tissues. Furthermore with these conventional treatments, subjects suffer from significant local, and at times, systemic side effects, incomplete resolution and frequent recurrences of the tumors, and of course, the expense incurred.
It is also known that phototherapy is used for removing laryngeal papillomatosis tumors. While such phototherapy reduces tumor growth by about 50%, it also results in a generalized skin photosensitivity for at least six weeks, as well as other minor reactions. Despite the apparent success of this technique, the presence of latent viral DNA is nonetheless still maintained in the surrounding tissues.
An article by B. M. Lawrence entitled xe2x80x9cProgress in Essential Oilsxe2x80x9d, Perfumer and Flavorist, Vol. 16, 49-58 (1991) reviews the work of several investigators on the chemical composition of sandalwood oil. This article reports on several of the oxidation products of the oil and compares the composition of Chinese sandalwood oil and Indian sandalwood oil. The santalol content (santalol, cis-xcex1 and cis-xcex2, comprises about 50 and 20% respectively by weight of sandalwood oil) of various species of the genus Santalum, are also disclosed. This article makes no suggestion that sandalwood oil would be effective in treating the common wart in humans.
An article by Dwivedi et al. entitled, xe2x80x9cChemopreventive effects of sandalwood oil on skin papillomas in micexe2x80x9d in the European Journal of Cancer Prevention 1997; 6(4): 399-401, reports that the essential oil, emulsion or paste of sandalwood (Santalum album L) has been used in India as an ayruvedic medicinal agent. In his investigation, a 5% w/v solution of sandalwood oil in acetone was shown to be a chemopreventive agent against 7, 12-dimethylbenz(a)anthracene initiated and 12-O-tetracecanoyl phorbol-13-acetate promoted skin papillomas in CD1 mice. The author suggests that sandalwood oil could be an effective chemopreventive agent against skin cancer.
None of these references suggest or disclose the use of xcex1- and xcex2-santalols, sandalwood oil, or a soap containing sandalwood oil as an agent for the treatment of human papillomavirus-induced tumors. There presently exists in the medical community a need for improved methods and compositions which provide therapeutic treatment of viral-induced tumors such as warts in humans. The present invention fills that need of the medical community.
One aspect of the present invention relates to the use of xcex1- and xcex2-santalols, or mixtures thereof, the active ingredients of sandalwood oil, for the treatment of viral-induced tumors. Another aspect of the invention relates to the use of xcex1- and xcex2-santalols, or mixtures thereof, to treat viral-induced tumors in mammals, especially humans. Yet anther aspect of the invention relates to the use of xcex1- and xcex2-santalols, the major constituents of sandalwood oil, in the treatment of warts, skin blemishes and other viral-induced tumors. One major benefit of the present invention is that that xcex1- and xcex2-santalols do not destroy healthy, uninfected tissues nor cause any systemic side effects or local side effects such as irritation, necrosis of tissue surrounding the wart, allergic rashes, scarring, disfigurement or discomfort to the human treated therewith. In fact, the use of xcex1- and xcex2-santalols, sandalwood oil or a soap containing the oil has been found to smooth the patient""s skin and is beneficial to healthy tissue.
There is further disclosed a method for the prevention and treatment of genital warts, cancer of the cervix and eradication of human papillomavirus from the female genital tract in infected females, comprising the application of a cream or douche containing xcex1- or xcex2-santalols or mixtures or derivatives thereof, to the affected area of the human body. There is also disclosed a method for preventing cancer of the cervix, said method comprising the application of xcex1- or xcex2-santalols or mixtures or derivatives thereof, to the genital area of a female for a period of time and at a sufficient concentration to eradicate the human papillomavirus from the genital area of the female.
Another aspect of the present invention is directed to a simple method for providing therapeutic treatment of viral-induced tumors in humans. An additional aspect of the present invention relates to a method for the destruction of latent viral DNA which is contained in tissues so as to prevent recurrence of these tumors.
Thus, there is disclosed a method for the treatment of viral induced tumors in a mammal, said method comprising the topical application of xcex1- and xcex2-santalols and mixtures thereof.
The method of this invention is specifically directed to the use of a composition that is suitable for topical application. The initial discovery of the inventors was based upon the use of a soap manufactured by Karnataka Soaps and Detergents, Ltd., Bangalore, India, known and marketed as xe2x80x9cMysore Sandal Soapxe2x80x9d. The product packaging states that this soap contains natural Mysore sandalwood oil distilled by the government of Karnataka. It is known that this soap also contains vegetable ingredients. A second soap manufactured by Alfa Cosmetics, of Bombay, India, known as xe2x80x9cEastern Mysore""s Pure Sandal Soapxe2x80x9d has also been found effective in treating viral induced epidermal tumors, however, it is somewhat less effective. The xe2x80x9cEastern Mysore""s Pure Sandal Soapxe2x80x9d lists as its ingredients: palm stearin, rice bran fatty, coconut oil, caustic soda, perfume, sandalwood oil and preservatives. At the time the parent patent application was filed, the inventors had not isolated the active component from the sandalwood soap. Then after filing a continuation-in-part application, the inventors, through further investigative effort, had determined that the sandalwood oil component of the soap was responsible for its therapeutic effects. As of the filing date of the present application, the inventors have isolated the active ingredients from the sandalwood oil, xcex1- and xcex2-santalols. Analysis has led to the discovery that xcex1- and xcex2-santalols are the active components in sandalwood oil. As will be set forth below, the inventors have elucidated that the xcex1- and xcex2-santalols may be the agents with outstanding use in the treatment of human warts.
Approximately 70% of sandalwood oil is comprised of two bicyclic sequiterpene alcohols termed xcex1- and xcex2-santalols. Table I sets forth the constituents of sandalwood oil.
The chemical make-up of a sandalwood oil varies slightly from source to source, however, xcex1- and xcex2-santalol make up over 65% of the oil.
The chemical formula for xcex1- and xcex2-santalol is C15H24O and the chemical structures are shown below. 
Santalols may be obtained by fractional distillation of sandalwood oil, with the xcex1- and xcex2-isomers appearing in different ratios and with the xcex1-isomer being more abundant. The santalols are colorless to pale yellow in appearance. One source of availability is Aldrich Chemical Company in Milwaukee, Wis. They sell the santalols as a mixture of xcex1- and xcex2-isomers in the ratio of 2.5 to 1, respectively.
Santalols are commonly used in the flavor and fragrance industries and are considered woody, cedar-like, warm and herbaceous. They may be used in perfumes, baked goods, frozen dairy, soft candy, gelatin pudding, chewing gum and non-alcoholic beverages. As such, they are non-toxic and harmless when used either for external application on the skin or internal consumption for flavor.
The purpose of the present invention is to test the efficacy of xcex1- and xcex2-santalols in the treatment of warts, as a natural continuation of sandalwood oil, which in the earlier study was shown to be efficient in the treatment of warts.
In another embodiment of this invention, the active component or components of the sandalwood oil are disclosed for the treatment of viral-induced tumors.
In particular, the xcex1- and xcex2-santalols described herein may be used for the preparation of therapeutic compositions in the treatment of viral-induced tumors in humans. Preferably, the compositions useful in the method may be topically applied to the human in need of such therapy.
The method of the present invention neither destroys healthy, uninfected tissue nor results in any local or systemic side effects, scarring, disfigurement or discomfort to the human treated. Furthermore, the use of the present method results in the destruction of latent viral DNA found in the tumor and the surrounding tissues so that instances of incomplete resolution and tumor recurrence may be prevented. The method includes the use of xcex1- and xcex2-santalols for the administration to an area of the human which is anticipated to evidence viral-induced tumor growth, or an area which presently exhibits viral-induced tumor growth (i.e., warts and Molluscom contagiosum tumors) to eliminate the viral-induced tumor. In accordance with the method according to this invention, regular use of the xcex1- and xcex2-santalols is meant to mean application of the xcex1- and xcex2-santalols at least once a day to the body surface containing the viral-induced tumors (i.e., warts and Molluscom contagiosum tumors). A further embodiment of the method of this invention comprises washing the affected area of the body with the soap, rinsing the area, placing a small amount of the xcex1- and xcex2-santalols on the tumor to be treated and then gently rubbing to facilitate penetration. It has been determined through clinical evaluation that once the method of this invention is initiated, the warts begin to shrink, no matter what size, and will totally disappear after a period of 8 to 10 weeks of treatment.